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Mike Pole

Specialised Subjects

Biochemistry, Biology, Biotechnology, Chemistry, Medicine, Pharmacology

At present I am working at one of the world’s leading pharmaceutical companies. Before accepting this position I worked for two other leading pharmaceutical companies. I am working in regulatory affairs dealing with the clinical aspects of Regulation, better known as Regulatory/Clinical Writer. My educational background is also related to pharmaceuticals as I did my Masters in pharmaceutical analysis at Strathclyde University. I also hold a bachelor degree in Pharmacy. I am a member of TOPRA and the British Red Cross and in my spare time I like reading current affairs and writing.

A clinical overview of Doxorubicin hydrochloride

Doxorubicin is a cytotoxic anthracycline antibiotic.

Doxorubicin can be used in single treatment or can be integrated in a combination therapy and is indicated for the treatment of various cancers such as: breast, lung, bladder, thyroid, gastric and ovarian carcinomas, osteosarcomas and soft tissue sarcomas, Wilms’ tumours, Hodgkin and non-Hodgkin lymphomas, neuroblastomas and acute lymphocytic and myeloblastic leukaemia.

The proposed changes, discussed below, are intended to align the summary of product characteristics (SmPC) for doxorubicin hydrochloride formulations, with the company’s
latest Core Data Sheet (CDS) for this drug substance.

The updated Core Data Sheet includes new information on the delayed cardiotoxicity, potential drug-drug interaction between doxorubicin and sorafenib, cardiac abnormalities, infertility in men and women and on the embryotoxic nature of doxorubicin.

This Clinical Overview Addendum has been prepared to support revisions to the doxorubicin product label to include information on section 4.4 ‘Special warnings and precautions for use’, section 4.5 ‘Interactions with other medicinal products and other forms of interaction’, section 4.6 ‘Pregnancy and lactation’, section 4.7 ‘Effects on ability to drive and use machines’, section 4.8 ‘Undesirable effects’, and section 4.9 ‘Overdose’.

This opportunity is being taken to introduce certain administrative updates to the SmPC. These include an update to the naming of the pharmaceutical form to align the text with current SmPC guidance dated September 2009; this update is reflected throughout the SmPC.  The spellings have been standardised throughout the text and in some cases minor updates have been made to include clarity of wording. These changes affect sections 4.4 and 4.8 of the SmPC and do not impact on the clinical content.

Overview of the proposed update
The Marketing Authorisation Holder is proposing to update the SmPC to include additional information in line with recent changes to the company core data sheet. Sections of the SmPC, in which only administrative changes have been made, are not detailed further in the table below, however full details are provided in the highlighted copy of the SmPC enclosed with this application. Where new or modified content is proposed within a section of the SmPC, this is described and reviewed in the table below. Details of all supporting data are included, and a full list of references is provided at the end of this document.

The changes are proposed in the left side of table and justification to changes are provided with supporting references in the right hand side of the table.

Proposed Changes Explanation (clinical overview)
Delayed cardiotoxicity cardiomyopathy is characterised by symptoms and signs of ventricular dysfunction (reduced left ventricular ejection fraction (LVEF)) and/or potentially fatal congestive heart failure (CHF), such as dyspnoea dyspnea, pulmonary oedema edema, dependent edema, (ankle) oeedema, cardiomegaly, hepatomegaly, oliguria, ascites, pleural effusion and gallop rhythm. In a critical review on doxorubicin cardiomyopathy, Saltiel reported that the toxic effect of doxorubicin on heart can be classified into acute or chronic cardiomyopathy. The chronic cardiomyopathy of doxorubicin limits the utility of this antineoplastic agent in patients. The signs and symptoms of cardiomyopathy are biventricular failure, tachycardia, shortness of breath, neck vein distention, gallop rhythms, ankle edema, hepatomegaly, cardiomegaly and pleural effusions. [1]The typographical errors have been corrected in the paragraph to improve the clarity of wording.
Children and adolescents are at an increased risk of developing delayed cardiotoxicity following doxorubicin administration.  Females may be at greater risk than males. Follow-up cardiac evaluations are recommended periodically to monitor for this effect. Silber et al. conducted a clinical study on 150 children treated with doxorubicin and reported that the possibility of A-CHF (anthracycline induced clinical heart failure) increases with increasing cumulative dose of anthracycline, younger age and female sex. [2]Kremer et al reported that there is risk of clinical heart failure in associated with anthracycline chemotherapy in a cohort of 607 children; patients treated with a higher dose were at higher risk and the estimated risk increased with time after the start of chemotherapy [3].Lipshultz conducted a clinical study on doxorubicin and reported that late cardiotoxicity is the side effect of cumulative dose of doxorubicin; also female patients treated with doxorubicin for childhood cancer are more vulnerable to cardiotoxicity and more likely to remain in remission than the male patients. This is due to the fact that cardiotoxicity causes reduction of contractility in left ventricle of the heart, leading to progressive ventricular dysfunction. Females have more reduction in comparison to men and hence the female sex is more susceptible to side effects of doxorubicin. [4], [5].
Secondary leukaemialeukemiaSecondary acute myeloid leukaemia, with or without a pre-leukaemic phase, has been reported in patients receiving combined treatment with anthracyclines (including doxorubicin). Smith et al reported that after treatment of tumors with doxorubicin/cyclophosphamide combination therapy in 8563 patients, 43 patients presented with either AML (acute myeloid leukemia) or MDS (myelodysplastic syndrome) and the average dormant period is about 38 months.[6]Diamondidou et al reported involvement of topoisomerase –II inhibitors, together with anthracyclines (daunorubicin, doxorubicin, and epirubicin), in the treatment – related leukemia. Also, they demonstrated an increased prevalence of Acute Myleoid Leukemia subsequent chemotherapy with topoisomerase-II inhibitors including anthracyclines. [7] Secondary acute myeloid leukemia has been reported in patients receiving combination therapy including doxorubicin. The updated wording is therefore more consistent with the published literature.
Intra-arterial route.  Intra-arterial administration of doxorubicin (transcatheter arterial embolization) may be employed for the localized or regional therapy of primary hepatocellular carcinoma or liver metastases.  Intra-arterial administration may produce (in addition to systemic toxicity qualitatively similar to that observed following intravenous administration of doxorubicin) gastro-duodenal ulcers (probably due to reflux of the drugs into the gastric artery) and narrowing of bile ducts due to drug-induced sclerosing cholangitis. This route of administration can lead to widespread necrosis of the perfused tissue. Acunas et al reported that there are many treatments for hepato cellular carcinoma (HCC) available such as surgery, TACE (transcatheter arterial embolization), and OLT (orthotopic liver transplantation). The most commonly used is transcatheter arterial embolization, which is a combination of embolization and chemotherapy. [8]TACE with doxorubicin poses less systemic toxicity than other treatments available for HCC (with no additional efficacy) but there many side effects such as hepatic insufficiency/abscess, tumor rupture, bile duct injury, surgical cholecystitis, upper GI bleeding, pulmonary embolism, splenic infarction and spinal embolization myelosuppresion, cardio and gastrointestinal toxicity. The problem associated with the use of TACE is that it causes complete tumor necrosis and intrahepatic metastases. [8], [9].It is proposed to update the SmPC to provide information on the side effects associated with this route of administration.
In clinical studies, both an increase of 21% and 47%, and no change in the AUC of doxorubicin were observed with concomitant treatment with sorafenib 400 mg twice daily.  The clinical significance of these findings is unknown. The first clinical study evaluated the efficacy of sorafenib combined with doxorubicin in patients with refractory solid tumors (Richly, 2006).  Pharmacokinetic parameters were assessed in 23 patients.  Co-administration of sorafenib 400 mg BID (50 mg tablet formulation) and doxorubicin 60 mg/m2 resulted in increases in the doxorubicin Cmax by 103% and AUC by 47%; this interaction did not enhance the clinical toxicity profile.  In contrast, the administration of doxorubicin with sorafenib 400 mg BID (200 mg tablet formulation) resulted in a slight reduction in doxorubicin Cmax and no effect on AUC; and when doxorubicin was administered with lower doses of sorafenib (100 mg and 200 mg BID), the Cmax and AUC values were not significantly altered. [10]The second clinical study evaluated the efficacy of sorafenib combined with doxorubicin in patients with advanced hepatocellular carcinoma (Richly, 2009).  Among 11 evaluable patients, simultaneous administration of sorafenib 400 mg BID and doxorubicin 60 mg/m2 increased the doxorubicin Cmax by 33% and AUC by 21%; no relevant changes were observed in the sorafenib Cmax and AUC.  [11]These two clinical studies have found that co-administration of doxorubicin and sorafenib was associated with both increases (21% and 47%) and no change in the AUC of doxorubicin.  The authors concluded that this interaction did not appear to significantly alter the toxicity profile.Pfizer’s safety database was searched for doxorubicin reports received through 30 June 2009 containing sorafenib as a co-suspect or concomitant drug.  This search included spontaneous cases from health care professionals, or otherwise medically confirmed cases, including those provided by Health Authorities and literature non-clinical trial sources.  This search identified no cases reporting a drug-drug interaction between doxorubicin and sorafenib.
Impairment of FertilityIn women, doxorubicin may cause infertility during the time of drug administration. Doxorubicin may cause amenorrhea.  Ovulation and menstruation appear to return after termination of therapy, although premature menopause can occur.In men, doxorubicin is mutagenic and can induce chromosomal damage in human spermatozoa. Oligospermia or azoospermia may be permanent; however, sperm counts have been reported to return to normospermic levels in some instances. This may occur several years after the end of therapy. Men undergoing doxorubicin treatment should use effective contraceptive methods. Hortobagyi et al conducted a clinical study and reported that out of 796 patients treated with adjuvant chemotherapy containing doxorubicin, 80% premenopausal patients turn into amenorrheic during the treatment depending upon age of patient. There were no incidence of amenorrhea in patients whose age is less than 30 years. 33 % and 96 % patients turn into amenorrheic during treatment with age group of 30-39 and 40-49 respectively. Patients older than 49 years became 100% amenorrheic.Some patients resumed menses but that was as well age dependent, only few patients more than the age of 40 resume menses whereas 50 % patients with age less than 30 years started menstruation again. [12]Rodger M. Pryzant et al. conducted a clinical study and reported that Doxorubicin is highly potent in destroying stem cells of spermatogonia, which results in temporary to permanent azoospermia. Also, in regimens of chemotherapy, high dose of doxorubicin shows only 10% recovery from low sperm count or azoospermia. They also reported that rate of recovery in men can be quick if the production of sperm resumes with in two and half years, hence they should use contraceptive methods whilst undergoing treatment. [13]
PregnancyThe embryotoxic potential of doxorubicin was confirmed in vitro and in vivo. When given to female rats before and during mating, pregnancy, and lactation, doxorubicin was toxic to both dams and fetuses.Doxorubicin has been implicated in causing fetal harm when administered to a pregnant woman. If a woman receives doxorubicin during pregnancy or becomes pregnant while taking the drug, she should be apprised of the potential hazard to the fetus. Doxorubicin is embryotoxic and teratogenic in the rat during organogenetic period either in vivo or in vitro. In vitro Doxorubicin is able to produce embryotoxic effects at much lower concentrations. [14]Andreas Artlich et al., studied the risk of pregnancy from cytotoxic drugs and reported that there is proven risk to the fetus but it is not mandatory that drug will causes fetal loss, fetal malformation or neurological abnormalities, even if exposed during first trimester. [15]
The effect of doxorubicin on the ability to drive or use machinery has not been systematically evaluated. As the relevant studies have not been performed to evaluate the effect of doxorubicin on the ability to drive and operate machinery, the statement proposed more accurately reflects the current situation and is therefore recommended for addition to the SmPC. No additional reference is cited.
Skin and subcutaneous tissue disorders: alopecia and interrupted beard growth, local toxicity, rash/pruritus, skin changes, skin and nail hyperpigmentation, photosensitivity, hypersensitivity of the irradiated skin (“radiation recall reactions”), urticaria, acral erythema, hand-foot-syndrome (palmoplantar erythrodysesthesia or acroerythema). The term ‘acral erythema’ is preferred to ‘palmar-plantar erythrodysaesthesia’ to describe syndrome on grounds that it is easier to understand, if less precise.[16]
Adverse Reactions in Patients with Early Breast Cancer Receiving Doxorubicin-Containing Adjuvant Therapy:  Safety data were collected from approximately 2300 women who participated in a randomised, open-label trial (NSABP B-15) evaluating the use of AC versus CMF in the treatment of early breast cancer involving axillary lymph nodes.  The most relevant adverse events reported in this study were consistent with the safety adverse event profile for doxorubicin. Additional adverse events include: Fischer et al. reported the clinical trial B-15 conducted by NSABP to compare the 2 months of AC (doxorubicin and cyclophosphamide) treatment to 6 months of CMF (cyclophosphamide, methotrexate, and fluorouracil) treatment in breast cancer patients thought to be non responsive to tamoxifen (TAM). It was observed that the addition of AC (Adriamycin – cyclophospjamide) to Tamoxifen in women with TAM-responsive stage II breast cancer is better than to use Tamoxifen alone. [17]In AC treatment compared to CMF treatment the adverse effects myelosuppression, nausea, diarrhea, hemorrhagic, and weight gain were less severe.[17]
Acute doxorubicin overdosage results in severe myelosuppression (mainly leukopenia and thrombocytopenia), gastrointestinal toxic effects (mainly mucositis) and acute cardiac alterations and abnormalities. Marini et al concluded in a report that doxorubicin overdosing may result in neutropenia, myelotoxicity, and gastrointestinal toxicity, mainly mucositis. Events may be reversible following an appropriate supportive treatment. [18].
The proposed update to the SmPC reflects this more accurately.

The proposed changes will enhance the prescribing information available for the healthcare professional, by inclusion of additional information in doxorubicin. Where appropriate the Marketing Authorisation Holder is proposing to reflect these SmPC changes in the PIL.

The changes proposed are reviewed in the above table and are justified on the basis of the supporting information provided within the application. There is no change to the risk-benefit assessment and the Marketing Authorisation Holder will continue to closely monitor all reports of adverse events and will revise the product documents if an evaluation of surveillance data yields significant new information.

It is therefore recommended that the changes be implemented.

Emmanuel Saltiel, PharmD, Los Angeles, and William Mcguire, MD, Chicago. Doxorubicin (Adriamycin) Cardiomyopathy.

Silber JH, Jakacki RI, Larse RL, et al: Increased risk of cardiac dysfunction after anthracyclines in girls. Med Pediatr Oncol 1993; 21:477-79.

Kremer LCM, van Dalen EC, Offringa J, et al: Anthracycline-induced clinical heart failure in a cohort of 607 children: long-term follow-up study. J Clin Oncol 2001; 19(1): 191-96.

Kesavan S, Lincoff MA, Young, JB: Anthracycline-induced cardiotoxicity. Ann of Inter Med 1996; 125(1): 47-58.

Lipshultz SE, Lipsitz SR, Mone SM, et al: Female sex and higher drug dose risk for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Eng J Med 1995; 332: 1738-43.

Smith RE, Bryant J, DeCillis A, et al: Acute Myeloid Leukemia and Myelodysplastic Syndrome after Doxorubicin-Cyclophosphamide Adjuvant Therapy for Operable Breast Cancer: The National Surgical Adjuvant Breast and Bowel Project Experience. J Clin Oncol 2003; 21(7): 1195-1204.

Diamandidou E, Buzdar AU, Smith TL, et al: Treament-related leukemia in breast cancer patients treated with fluorouracil-doxorubicin-cyclophosphamide combination adjuvant chemotherapy: the University of Texas M.D. Anderson Cancer Center experience. J Clin Oncol 1996; 14(10): 2722-30.

Acunaş B, Rozanes I. Hepatocellular carcinoma: treatment with transcatheter arterial chemoembolization. Eur J Radiol 1999;32(1):86-89.

Nerenstone S, Friedman M. Medical treatment of hepatocellular carcinoma. Gastroenterol Clin North Am 1987;16(4):603-612.

Richly H, Henning BF, Kupsch P, et al. Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors. Annals of Onoclogy 2006;17:866-73.

Richly H, Schultheis B, Adamietz IA, et al. Combination of sorafenib and doxorubicin in patients with advanced hepatocellular carcinoma: Results from a phase I extension trial. European Journal of Cancer 2009;45:579-87.

Hortobagyi GN, Buzdar AU, Marcus CE, Smith TL. Immediate and long-term toxicity of adjuvant chemotherapy regimens containing doxorubicin in trials at M.D. Anderson Hospital and Tumor Institute. NCI Monogr. 1986;(1):105-9.

Pryzant RM, Meistrich ML, Wilson G, et al. Long-term reduction in sperm count after chemotherapy with and without radiation therapy for non-Hodgkin’s lymphomas. J Clin Oncol 1993;11(2):239-247.

Menegola E, Broccia ML, Prati M, et al. Comparative embryotoxicity of four anthracyclines: In vitro study on their effects on glutathione status. Toxicol In vitro 1997;11(1-2):33-41.

Artlich A, Moller J, Tschakaloff A, et al. Teratogenic effects in a case of maternal treatment for acute myelocytic leukemia– neonatal and infantile course. Eur.J.Pediatr 1994;153:488-91.

Rogers D. Clinical Expert Statement for Doxorubicin and the Adverse Event Palmar Plantar Erythrodysaesthesia, 26 November 2003.

Fisher B, Brown AM, Nikolay V, et al: Two Months of Doxorubicin-Cyclophosphamide With and Without Interval Reinduction Therapy Compared with 6 Months of Cyclophosphamide, Methotrexate, and Fluorouracil in Positive-Node Breast Cancer Patients with Tamoxifen-Nonresponsive Tumors: Results From the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 1990; 8:1483-96.

Marini G. Clinical Expert Statement on Doxorubicin Overdose, dated 14 November 2005.